5-(trifluoromethyl)pyrimidine derivatives and method for producing same

ABSTRACT

Provided are 5-(trifluoromethyl)pyrimidine derivatives useful as intermediates for pharmaceuticals and agrochemicals and as intermediates for electronic materials and methods for producing the same. 2,4-dichloro-5-(trifluoromethyl)pyrimidine is reacted with 2,2,2-trifluoroethanol, benzyl alcohol, or benzenethiol to obtain the intended 2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine, 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine, 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine, or 2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine.

TECHNICAL FIELD

The present invention relates to novel 5-(trifluoromethyl)pyrimidinederivatives and methods for producing the same.5-(trifluoromethyl)pyrimidine derivatives such as2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine,2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine,2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine, and2-chloro-5-phenylthio-5-(trifluoromethyl)pyrimidine are compounds usefulas raw materials for synthesis of various pharmaceuticals,agrochemicals, and electronic materials.

BACKGROUND ART

The 5-(trifluoromethyl)pyrimidine derivatives and methods for producingthe same according to the present invention have hitherto been unknown.

As for analogues of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine and2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention, 2-methoxy-4-chloro-5-(trifluoromethyl)pyrimidine hasbeen known and there is a known method in which2,4-dichloro-5-(trifluoromethyl)pyrimidine and methanol are reacted inthe presence of triethylamine to give a mixture of2-methoxy-4-chloro-5-(trifluoromethyl)pyrimidine and2-chloro-4-methoxy-5-(trifluoromethyl)pyrimidine and the mixture ispurified by silica gel column chromatography to obtain the intended2-methoxy-4-chloro-5-(trifluoromethyl)pyrimidine (see Patent Document 1,for example).

However, there has been a problem in that when the method described inPatent Document 1 is used in an attempt to produce2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention, the intended2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine is notformed. There have also been problems in that: when the method is usedin an attempt to produce2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine, the intended2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine is not formed; andwith the use of a known method using a metal salt of an alcohol, inparticular a method in which a lithium salt of benzyl alcohol and2,4-dichloro-5-(trifluoromethyl)pyrimidine are reacted in atetrahydrofuran solvent, the resulting product is a mixture of theintended 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine and itsregioisomer, 2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine(intended product/isomer=73/27), and separation and purification by aprocess such as silica gel column chromatography must be performed toobtain the intended product.

On the other hand, as an analogue of2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine accordingto the present invention, 2,4-dichloro-5-(trifluoromethyl)pyrimidine(which may hereinafter be abbreviated as “CFP”) has been known and thereis a known method in which the latter compound is substituted at the2-position and 4-position of the pyrimidine ring by various substituentsto produce candidate drugs for pharmaceuticals (see Patent Document 2,for example).

However, highly selective introduction of various substituents at the2-position or 4-position with CFP is difficult by conventional methods,according to which the resulting product is a mixture of a 2-substitutedproduct and a 4-substituted product. There has thus been a problem inthat separation and purification by a process such as silica gel columnchromatography must be performed to obtain the intended product of highpurity.

Furthermore, as for an analogue of2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine according to thepresent invention, 2-chloro-4-methylthio-5-(trifluoromethyl)pyrimidinehas been known and is obtained by a reaction between2,4-dichloro-5-(trifluoromethyl)pyrimidine and sodium thiomethoxide (seePatent Document 1, for example).

However, the method described in Patent Document 1 has problems in thatit is a method involving purification by silica gel columnchromatography of the mixture of2-chloro-5-methylthio-5-(trifluoromethyl)pyrimidine and2-methylthio-4-chloro-5-(trifluoromethyl)pyrimidine obtained by thereaction and is required to be further improved for use as an industrialproduction method, and in that the yield is 28%, which is low.

PRIOR ART DOCUMENT Patent Document

Patent Document 1: National Publication of International PatentApplication No. 2008-528613

Patent Document 2: Japanese Patent No. 4842816

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention is directed to providing:5-(trifluoromethyl)pyrimidine derivatives such as2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine,2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine,2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine, and2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine which are expectedas introducers of a 5-(trifluoromethyl)pyrimidine skeleton; and methodsfor producing the same.

Means for Solving the Problems

More specifically, the present invention provides the following.

[1] A 5-(trifluoromethyl)pyrimidine derivative represented by thefollowing general formula (1):

wherein

R¹ is a 2,2,2-trifluoroethoxy group and R² is a chlorine atom or a2,2,2-trifluoroethoxy group, or

R¹ is a benzyloxy group and R² is a chlorine atom, or

R¹ is a chlorine atom and R² is a phenylthio group.

[2] The 5-(trifluoromethyl)pyrimidine derivative according to [1],wherein, in the general formula (1), R¹ is a 2,2,2-trifluoroethoxy groupand R² is a chlorine atom or a 2,2,2-trifluoroethoxy group, the5-(trifluoromethyl)pyrimidine derivative being represented by thefollowing general formula (2):

[3] The 5-(trifluoromethyl)pyrimidine derivative according to [1] or[2], wherein, in the general formula (1), R¹ and R² are each a2,2,2-trifluoroethoxy group, the 5-(trifluoromethyl)pyrimidinederivative being represented by the following formula (3):

[4] A method for producing the 5-(trifluoromethyl)pyrimidine derivativeaccording to [2] or [3], the method comprising reacting2,4-dichloro-5-(trifluoromethyl)pyrimidine with a metal2,2,2-trifluoroethoxide.

[5] A method for producing2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidinerepresented by the formula (2) according to [2], the method comprisingreacting 2,4-dichloro-5-(trifluoromethyl)pyrimidine with a metal salt of2,2,2-trifluoroethanol.

[6] The method for producing2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to [5], wherein the metal salt is a lithium salt, a sodiumsalt, or a potassium salt.

[7] The 5-(trifluoromethyl)pyrimidine derivative according to [1],wherein, in the general formula (1), R¹ is a benzyloxy group and R² is achlorine atom, the 5-(trifluoromethyl)pyrimidine derivative beingrepresented by the following formula (4):

[8] A method for producing the 5-(trifluoromethyl)pyrimidine derivativeaccording to [7], the method comprising reacting2,4-dichloro-5-(trifluoromethyl)pyrimidine with a metal salt of benzylalcohol in a mixed solvent of tetrahydrofuran and hexane.

[9] The method for producing the 5-(trifluoromethyl)pyrimidinederivative according to [8], wherein the metal salt is a lithium salt, asodium salt, or a potassium salt.

[10] The 5-(trifluoromethyl)pyrimidine derivative according to [1],wherein, in the general formula (1), R¹ is a chlorine atom and R² is asubstituted phenylthio group, the 5-(trifluoromethyl)pyrimidinederivative being represented by the following general formula (5):

wherein R³ represents a hydrogen atom or a methyl group.

[11] A method for producing 2-chloro-5-(trifluoromethyl)pyrimidinerepresented by the general formula (5) according to [10], the methodcomprising reacting 2,4-dichloro-5-(trifluoromethyl)pyrimidine with ametal salt of an aromatic thiols represented by the following generalformula (6):

wherein R³ is the same as defined in the formula (5).

[12] The method for producing the 2-chloro-5-(trifluoromethyl)pyrimidinederivative according to [11], wherein the metal salt is a lithium salt,a sodium salt, or a potassium salt.

Advantageous Effects of the Invention

According to the present invention, there are provided:5-(trifluoromethyl)pyrimidine derivatives such as2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine,2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine,2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine, and2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine which are novel asraw materials for synthesis of pharmaceuticals and agrochemicals; andmethods for producing the same.

It is expected that2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention allows introduction of anothersubstituent at the 4-position and that a 2- and 4-substituted5-(trifluoromethyl)pyrimidine derivative is derived by furthersubstituting the 2,2,2-trifluoroethoxy group at the 2-position by somesubstituent.

It is also expected that2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention allows introduction of another substituent at the4-position and that a 2- and 4-substituted 5-(trifluoromethyl)pyrimidinederivative can be produced by further deprotecting the benzyloxy groupat the 2-position through hydrogenation reaction or the like orsubstituting the benzyloxy group at the 2-position by some substituent.

It is further expected that2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine according to thepresent invention allows introduction of another substituent at the2-position and that a 2- and 4-substituted 5-(trifluoromethyl)pyrimidinederivative is derived by further oxidizing the aromatic thio group atthe 4-position and then substituting the oxidized group by somesubstituent.

MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

2,4-dichloro-5-(trifluoromethyl)pyrimidine used as a raw material in thepresent invention can be prepared, for example, industrially-available5-(trifluoromethyl)uracil with phosphorus oxychloride or the like bydehydration and chlorination.

The method for producing2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention will now be described.

It is recommended that 2,2,2-trifluoroethanol used for the production of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention be used in an amount of 1.0 mole to1.5 moles based on the mole of2,4-dichloro-5-(trifluoromethyl)pyrimidine subjected to the reaction.

Specific examples of a metal reagent applicable to preparation of themetal salt of 2,2,2-trifluoroethanol which is used for the production of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention include lithium metal, sodium metal,potassium metal, lithium hydride, sodium hydride, potassium hydride,n-butyllithium, tert-butyllithium, lithium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, and potassiumhexamethyldisilazide. It is recommended that the metal reagent be usedin an amount of 0.7 moles to 1.0 mole besed on the mole of benzylalcohol subjected to the reaction. A commercially-available solutiondiluted to a given concentration with any of various solvents may alsobe used as the metal reagent.

Specific examples of the solvent applicable to the production of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention include: ether solvents such asdiethyl ether, diisopropyl ether, methyl tert-butyl ether,tetrahydrofuran, and methyl cyclopentyl ether; aromatic solvents such asbenzene, toluene, ethylbenzene, mesitylene, and cumene; and aliphatichydrocarbon solvents such as n-pentane, n-hexane, and cyclohexane. It isrecommended that the solvent be used in an amount of 5 parts by weightto 40 parts by weight besed on the weight of2,4-dichloro-5-(trifluoromethyl)pyrimidine subjected to the reaction. Amixture of two or more of the above solvents may also be used.

The reaction temperature and reaction time applicable to the productionof 2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention vary depending on the type of themetal reagent used, the type of the solvent, and the substrateconcentration. In general, the reaction is completed when performed in atemperature range of −80 to 65° C. for 4 to 48 hours.

Post-treatment subsequent to the production of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidineaccording to the present invention is possible by means of a well-knowntechnique. For example, the reactant may be obtained as a liquid,through was quenched with a saturated aqueous ammonium chloridesolution, extracted with a solvent such as dichloromethane, dried oversodium sulfate, filtrated, and concentrated, and purification of thecrude product by distillation where necessary.

The method for producing2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention will now be described.

It is recommended that benzyl alcohol used for the production of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention be used in an amount of 1.0 to 1.5 moles per mole of2,4-dichloro-5-(trifluoromethyl)pyrimidine subjected to the reaction.

Specific examples of a metal reagent applicable to preparation of themetal salt of benzyl alcohol which is used for the production of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention include lithium metal, sodium metal, potassium metal,lithium hydride, sodium hydride, potassium hydride, n-butyllithium,tert-butyllithium, lithium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, and potassiumhexamethyldisilazide. It is recommended that the metal reagent be usedin an amount of 0.7 to 1.0 mole based on the mole of benzyl alcoholsubjected to the reaction. The combination of benzyl alcohol and theabove metal reagent yields a lithium salt, sodium salt, or potassiumsalt of benzyl alcohol, and the salt is subjected to the reaction. Onemetal reagent may be used alone or two or more metal reagents may beused in combination. In addition, a commercially-available solution ofmetal reagents diluted to some concentration with any of varioussolvents may be used alone, or two or more such solutions may be used incombination, as the metal reagent.

The mixed solvent of tetrahydrofuran and hexane used for production of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention is applicable when the ratio, tetrahydrofuran/hexane,is in the range of ½ (vol/vol) to ⅛ (vol/vol). If the amount of hexaneused is smaller, the selectivity may decrease, while the use of toolarge the amount of hexane, the yield of the product decrease by theprecipitation of the metal salt of benzyl alcohol.

It is recommended that the mixed solvent of tetrahydrofuran and hexaneused for production of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention be used in an amount of 5 to 40 parts by weight basedon the weight of 2,4-dichloro-5-(trifluoromethyl)pyrimidine subjected tothe reaction.

The reaction temperature and reaction time applicable to the productionof 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention vary depending on the type of the metal reagent used,the composition of the mixed solvent, and the substrate concentration.In general, the reaction is completed when performed in a temperaturerange of −80 to 65° C. for 4 to 48 hours.

Post-treatment subsequent to the production of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine according to thepresent invention is possible by means of a well-known technique. Forexample, the reactant may be obtained as a solid, through was quenchedwith a saturated aqueous ammonium chloride solution, extracted with asolvent such as dichloromethane, dried over sodium sulfate, filtrated,and concentrated, and the purification of the crude product byrecrystallization where necessary.

The method for producing2,4-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrimidine according tothe present invention will now be described.

An available method for producing TFEFP according to the presentinvention is to produce TFEFP by reaction of2,4-dichloro-5-(trifluoromethyl)pyrimidine (CFP) and a metal2,2,2-trifluoroethoxide.

As one example of the production method, metal salt of2,2,2-trifluoroethanol which was prepared 2,2,2-trifluoroethanol withorganometal or a metal hydride in situ was reacted with CFP to produceTFEFP. As another example, the isolated metal salt of2,2,2-trifluoroethanol was reacted with CFP to produce TFEFP.

CFP used as a raw material in the method for producing TFEFP accordingto the present invention is an industrially-available material and isprepared, for example, by a method in which 5-(trifluoromethyl)uracil isdehydrated and chlorinated with phosphorus oxychloride or the like.

Specific examples of the metal salt of 2,2,2-trifluoroethanol applicableto the production according to the present invention include lithium2,2,2-trifluoroethoxide, sodium 2,2,2-trifluoroethoxide, and potassium2,2,2-trifluoroethoxide. It is recommended that the metal salt be usedin an amount of 2.0 moles or more, preferably in an amount of 2.2 to 3.0moles, based on the mole of CFP subjected to the reaction. It ispreferable to prepare the metal salt of 2,2,2-trifluoroethanol withinthe system prior to the reaction with CFP, and it is recommended toperform the preparation in a temperature range of −80° C. to roomtemperature by dissolving 2,2,2-trifluoroethanol in a solvent that isinactive in the reaction and using an organometal or metal hydride suchas lithium hydride, sodium hydride, potassium hydride, methyllithium,n-butyllithium, tert-butyllithium, lithium diisopropylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, or potassiumhexamethyldisilazide in an amount of 0.9 moles to 1.0 mole based on themole of 2,2,2-trifluoroethanol.

The solvent applicable to the production according to the presentinvention is not particularly limited which the solvent is inactive inthe reaction. Specific examples of the solvent include: ether solventssuch as diethyl ether, diisopropyl ether, tetrahydrofuran, cyclopentylmethyl ether, and methyl tert-butyl ether; and aliphatic hydrocarbonsolvents such as n-pentane, n-hexane, and cyclohexane. It is recommendedthat the solvent be used in an amount of 5 to 50 parts by weight basedon the weight of CFP subjected to the reaction. These solvents may beused alone or may be used as a mixture.

The reaction temperature and reaction time in the method for producingTFEFP according to the present invention vary depending on the type ofthe metal salt of 2,2,2-trifluoroethanol and the type and amount of thesolvent. In general, the reaction can be completed when performed in atemperature range of −80 to 100° C. for 1 to 24 hours.

Post-treatment subsequent to the reaction according to the presentinvention is not particularly limited to a commonly-known technique isused. For example, the intended TFEFP can be obtained throughneutralization with a saturated aqueous ammonium chloride solution,concentration, extraction with dichloromethane, drying, filtration, andconcentration. Purification by silica gel treatment, distillation or thelike may further be performed.

The method for producing2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine according to thepresent invention will now be described.

Specific examples of the aromatic thiol (2), represented by the generalformula (2), which is applicable to the production of the2-chloro-5-(trifluoromethyl)pyrimidine derivative (1) according to thepresent invention include benzenethiol, 2-methylbenzenethiol,3-methylbenzenethiol, and 4-methylbenzenethiol. It is recommended thatthe aromatic thiol (2) be used in an amount of 0.9 moles to 1.3 molesbased on the mole of 2,4-dichloro-5-(trifluoromethyl)pyrimidinesubjected to the reaction.

As for metal salt of an aromatic thiols used for the production of the2-chloro-5-(trifluoromethyl)pyrimidine derivative (1) according to thepresent invention, a commercially-available a metal salt of aromaticthiols may be used by itself or, where necessary, a metal salt ofaromatic thiols may be prepared within the system. Specific examples ofa metal reagent applicable to the preparation within the system includelithium metal, sodium metal, potassium metal, lithium hydride, sodiumhydride, potassium hydride, n-butyllithium, tert-butyllithium, lithiumdiisopropylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, and potassium hexamethyldisilazide. It isrecommended that the metal reagent be used in an amount of 0.8 moles to1.0 mole based on the mole of the aromatic thiol subjected to thereaction. A commercially-available solution of metal reagents diluted tosome concentration with any of various solvents may also be used as themetal reagent.

The solvent applicable to the production of the2-chloro-5-(trifluoromethyl)pyrimidine derivative (1) according to thepresent invention is not particularly limited which the solvent isinactive in the reaction. Specific examples of the solvent include:ether solvents such as diethyl ether, diisopropyl ether, cyclopentylmethyl ether, and tetrahydrofuran; aromatic hydrocarbon solvents such asbenzene, toluene, ethylbenzene, cumene, and mesitylene; and aliphatichydrocarbon solvents such as pentane, n-hexane, cyclohexane, andn-pentane. It is recommended that the solvent be used in an amount of 5parts by weight to 40 parts by weight based on the weight of2,4-dichloro-5-(trifluoromethyl)pyrimidine subjected to the reaction. Inaddition, where necessary, two or more solvents may be mixed and used.

The reaction temperature and reaction time applicable to the productionof the 2-chloro-5-(trifluoromethyl)pyrimidine derivative (1) accordingto the present invention vary depending on the type of the metal reagentused, the composition of the solvent, and the substrate concentration.In general, the reaction is completed when performed in a temperaturerange of −40 to 50° C. for 4 to 48 hours.

Post-treatment subsequent to the production of the2-chloro-5-(trifluoromethyl)pyrimidine derivative (1) according to thepresent invention is possible by means of a well-known technique. Forexample, a crude product may be obtained as a solid throughneutralization with a saturated aqueous ammonium chloride solution,extraction with a solvent such as dichloromethane, drying over sodiumsulfate, filtration, and concentration, and the crude product may bepurified by recrystallization where necessary.

EXAMPLES

Hereinafter, the present invention will be specifically described withreference to examples; however, the present invention is not limitedonly to these examples. For analyses, the following apparatuses wereused.

¹H-NMR, ¹⁹F-NMR, ¹³C-NMR: AVANCE II 400, manufactured by BRUKERCORPORATION

GC-MS: GCMS-QP2010Plus, manufactured by Shimadzu Corporation

Element analysis: CHN Coder MT-6, manufactured by Yanaco TechnicalScience Co., Ltd.

Example 1 Preparation of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7)

To a 2000 mL four-necked round-bottom flask equipped with a stirrer bar,2,2,2-trifluoroethanol (40.12 g, 0.401 mol) and tetrahydrofuran (1475mL) were added under nitrogen. After cooling to −20° C., n-butyllithium(1.6 M hexane solution, 250 mL, 0.400 mol) was added, followed bystirring at the same temperature for 30 minutes. Subsequently,2,4-dichloro-5-(trifluoromethyl)pyrimidine (CFP, 86.73 g, 0.400 mol) wasadded dropwise over 30 minutes, followed by further stirring at the sametemperature for 30 minutes and then the reaction mixture was stirred atroom temperature for 6 hours.

After the reaction was completed, the reaction mixture was quenched withsaturated aqueous sodium chloride solution (600 mL×3 times) and thenconcentrated under reduced pressure to obtain crude product (119.33 g)as a yellow liquid. At this stage, the conversion of CFP and yield ofthe product were determined by ¹⁹F-NMR of the crude product usinghexafluorobenzene as an internal standard, and it was found that theintended2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7) wasproduced at a conversion of 97% and in a yield of 80%. As forby-products, an isomer,2-chloro-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine, wascontained in an amount of 4% in a yield, and2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine as anoverreaction product was contained in an amount of 10% in a yield.

Furthermore, the crude product was purified by rectificationdistillation under reduced pressure using a packed column (Kiriyama Pac,10 plates, 20 mm ID×250 mmL) to be obtained purified2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7) asa colorless liquid (70.21 g, purity=97.0%, yield=61%).

¹H-NMR (CDCl₃, 400 MHz) δ 8.78 (d, J=0.8 Hz, 1H), 4.89 (q, J=8.0 Hz,2H).

¹⁹F-NMR (CDCl₃, 376 MHz) δ −63.72.

¹³C-NMR (CDCl₃, 100 MHz) δ 164.69, 161.84, 158.98 (q, J=5.0 Hz), 122.80(q, J=277.2 Hz), 122.04 (q, J=270.3 Hz), 119.13 (q, J=32.6 Hz), 64.71(q, J=37.0 Hz).

GC-MS (m/z) 280 (34, M⁺), 261 (34), 225 (32), 211 (91), 182 (100), 155(47), 147 (32), 120 (31), 83 (69).

Element Analysis

Calculated: carbon (29.97%), hydrogen (1.08%), nitrogen (9.98%)

Measured: carbon (29.92%), hydrogen (1.08%), nitrogen (9.96%)

Example 2 Preparation of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7)

To a 50 mL eggplant-shaped flask equipped with a stirrer bar,2,2,2-trifluoroethanol (0.65 g, 6.54 mmol) and tetrahydrofuran (4 mL)were added under nitrogen stream. After cooling to −20° C.,n-butyllithium (1.6 M hexane solution, 2.95 mL, 4.71 mmol) was added,followed by stirring at the same temperature for 30 minutes.Subsequently, at the same temperature, n-hexane (10 mL) was added andthen 2,4-dichloro-5-(trifluoromethyl)pyrimidine (CFP, 1.00 g, 4.61 mmol)was added. The reaction mixture was followed by further stirring at thesame temperature for 30 minutes and then stirred at room temperature for3 hours.

After the reaction was completed, the reactant was quenched withsaturated aqueous ammonium chloride solution (10 mL), concentrated toremove of tetrahydrofuran under reduced pressure, extraced withdichloromethane (10 mL×3 times), combined the organic layers and driedover sodium sulfate, filtrated, and then concentration, to give a crudeproduct of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7) asa pale yellow liquid (1.34 g). At this stage, the conversion of CFP andyield of the product were determined by ¹⁹F-NMR of the crude productusing hexafluorobenzene as an internal standard, and it was found thatthe intended2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7) wasproduced at a conversion of 97% and a yield of 84%. As the by-productsofthe isomer,2-chloro-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine, wascontained in an amount of 2% in a yield and2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine as anoverreaction product was contained in an amount of 13% in a yield.

Example 3 Preparation of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7)

To the same reactor as used in Example 2, 2,2,2-trifluoroethanol (0.55g, 5.53 mmol) and tetrahydrofuran (15 mL) were added. After cooling to−0° C., sodium hydride (60% in oil, 0.20 g, 4.99 mmol) was added,followed by stirring at the same temperature for 30 minutes.Subsequently, after cooling to −20° C., n-hexane (10 mL) was added andthen 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) wasadded. The reaction mixture was followed by further stirring at the sametemperature for 30 minutes and then by stirring at 0° C. for 16 hours.

After the reaction was completed, the reactant was treated with the samepost-treatment process as performed in Example 2 to giving a crudeproduct of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7)(1.37 g). At this stage, the conversion of CFP and yield of the productwere determined by ¹⁹F-NMR of the crude product using hexafluorobenzeneas an internal standard, and it was found that the intended2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7) wasproduced at a conversion of 99% and a yield of 87%. As the by-productsof isomer,2-chloro-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine wascontained in an amount of 1% in a yield and as the overreaction product,2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine wascontained in an amount of 8% in a yield.

Example 4 Preparation of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7)

To the same reactor as used in Example 2, 2,2,2-trifluoroethanol (0.55g, 5.53 mmol) and tetrahydrofuran (20 mL) were added. After cooling to−40° C., potassium hexamethyldisilazide (1.0 M tetrahydrofuran solution,4.70 mL, 4.70 mmol) was added, followed by stirring at the sametemperature for 30 minutes. Subsequently,2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) wasadded. The reaction mixture was followed by further stirring at the sametemperature for 30 minutes and then by stirring at −20° C. for 36 hours.

After the reaction was completed, the reactant was treated followed bythe same post-treatment process as performed in Example 2 to give acrude product of2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7)(1.33 g). At this stage, the conversion of CFP and yield of the productwere determined by ¹⁹F-NMR of the crude product using hexafluorobenzeneas an internal standard, and it was found that the intended2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine (7) wasproduced at a conversion of 99% and a yield of 86%. As the by-productsof isomer,2-chloro-4-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine wascontained in an amount of 2% in a yield and as an overreaction product,2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine wascontained in an amount of 5% in a yield.

Example 5 Preparation of2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3)

Placed to a 200 mL eggplant-shaped flask equipped with a stirrer bar,2,2,2-trifluoroethanol (5.99 g, 59.9 mmol) and tetrahydrofuran (85 mL)were added under a nitrogen stream. After cooling to −20° C.,n-butyllithium (1.6 M hexane solution, 34.5 mL, 55.2 mmol) was added,followed by stirring at the same temperature for 30 minutes.Subsequently, CFP (5.00 g, 23.0 mmol) was added to the reaction mixture,followed by stirring at the same temperature for 30 minutes and then bystirring at 40° C. for 24 hours.

After the reaction was completed, the reactant was quenched saturatedaqueous ammonium chloride solution (30 mL), concentrated under reducedpressure, extracted with dichloromethane (30 ml×3 times), dried oversodium sulfate, filtrated, and then concentrated under reduced pressureto giving a crude product.

Purification of the crude product by a silica gel bed (10 g, eluent:dichloromethane) gave pure2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3) (7.22g, 21.0 mmol, yield=91%) as a colorless liquid.

The result of analysis was as follows.

¹H-NMR (CDCl₃, 400 MHz) δ 8.60 (d, J=0.8 Hz, 1H), 4.91 (q, J=4.9 Hz,2H), 4.85 (q, J=4.8 Hz, 2H).

¹⁹F-NMR (CDCl₃, 376 MHz) δ −63.80, -74.82 (t, J=7.5 Hz), −74.89 (t,J=7.5 Hz).

¹³C-NMR (CDCl₃, 100 MHz) δ 167.07, 165.00, 158.38 (q, J=4.7 Hz), 122.99(q, J=275.8 Hz),

122.74 (q, J=275.6 Hz), 122.28 (q, J=269.4 Hz), 108.05 (q, J=34.7 Hz),64.39 (q, J =36.7 Hz), 63.39 (q, J=37.2 Hz).

GC-MS (m/z): 344 (M⁺, 45), 325 (58), 275 (100), 246 (93), 163 (90), 83(95).

Element Analysis

Calculated: carbon (31.41%), hydrogen (1.46%), fluorine (49.69%),nitrogen (8.14%)

Measured: (31.32%), hydrogen (1.46%), fluorine (49.64%), nitrogen(8.16%)

Example 6 Preparation of2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3)

To the same reactor as used in Example 5, 2,2,2-trifluoroethanol (8.29g, 82.9 mmol) and sodium hydride (manufactured by Wako Pure ChemicalIndustries, Ltd., 60% in oil (containing 40% of mineral oil), 3.32 g,82.9 mmol) which was used instead of n-butyllithium (1.6 M hexanesolution, 34.5 mL, 55.2 mmol) were added. The reaction was allowed toproceed at room temperature for 12 hours, followed by the samepost-treatment operation as performed in Example 1, to give2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3) (7.62g, 22.2 mmol, yield=96%) as a colorless liquid.

Example 7 Preparation of2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3)

To the same reactor as used in Example 5, 2,2,2-trifluoroethanol (6.13g, 61.3 mmol) and potassium hexamethyldisilazide (1M tetrahydrofuransolution, 64.5 mL, 64.5 mmol) which was used instead of n-butyllithium(1.6 M hexane solution, 34.5 mL, 55.2 mmol) were added. The reaction wasallowed to proceed at 0° C. for 18 hours, followed by the samepost-treatment operation as performed in Example 1, to give2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (3) (6.90g, 20.1 mmol, yield=87%) as a colorless liquid.

Example 8 Preparation of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4)

Placed to a 50 mL eggplant-shaped flask equipped with a stirrer bar,benzyl alcohol (0.50 g, 4.61 mmol) and tetrahydrofuran (4 mL) were addedunder nitrogen stream. After cooling to −20° C., n-butyllithium (1.6 Mhexane solution, 2.88 mL, 4.61 mmol) was added, followed by stirring atthe same temperature for 30 minutes.

Hexane (8 mL) was subsequently added and, after cooling to −80° C.,2,4-dichloro-5-(trifluoromethyl)pyrimidine (CFP, 1.00 g, 4.61 mmol) wasadded. The reaction mixture was followed by further stirring at the sametemperature for 30 minutes and then by stirring at room temperature for2 hours.

After the reaction was completed, the reactant was quenched withsaturated aqueous ammonium chloride solution (10 mL), concentratdedunder reduced pressure, extracted with dichloromethane (10 ml×3 times),combined organic layers and dried them over sodium sulfate, filtrated,and then concentrated to give a crude product of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4) as a pale yellowsolid (1.41 g). At this stage, the conversion of CFP and yield of theproduct were determined by ¹⁹F-NMR of the crude product usinghexafluorobenzene as an internal standard, and it was found that theconversion was 100%, the yield was 90%, and2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 10% a yield.

Furthermore, purification of the crude product by recrystallizationusing ethylbenzene gave purified2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4) as a white solid(1.00 g, yield=75%, purity=99%).

¹H-NMR (CDCl₃, 400 MHz) δ 8.70 (d, J=0.8 Hz, 1H), 7.50-7.45 (m, 2H),7.40-7.32 (m, 3H), 5.50 (s, 2H).

¹⁹F-NMR (CDCl₃, 376 MHz) δ −63.62.

¹³C-NMR (CDCl₃, 100 MHz) δ 165.94, 161.08, 158.70 (q, J=5.0 Hz), 135.05,128.75, 128.57, 122.31 (q, J=270.0 Hz), 117.50 (q, J=33.8 Hz), 70.95.

GC-MS (m/z): 288 (M⁺, 31), 253 (35), 182 (27), 107 (66), 91 (100).

Element Analysis

Calculated: carbon (49.93%), hydrogen (2.79%), nitrogen (9.70%)

Measured: carbon (19.80%), hydrogen (2.80%), nitrogen (9.68%)

Comparative Example 1 Preparation of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4)

A crude product of 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine(4) was obtained in the form of a pale yellow oily product (1.47 g) byperforming the same procedures as those in Example 1, except that theamount of tetrahydrofuran (which was 4 mL in Example 8) was changed to12 mL and that hexane (8 mL) was not used. As a result of ¹⁹F-NMRmeasurement using hexafluorobenzene as an internal standard, it wasfound that the conversion was 99%, the yield was 72%, and2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 27% in a yield.

Comparative Example 2 Preparation of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4)

A crude product of 2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine(4) was obtained in the form of a pale yellow oily product (1.16 g) byperforming the same procedures as those in Example 1, except that theamount of tetrahydrofuran (which was 4 mL in Example 8) was changed to 2mL and that the amount of hexane (which was 8 mL in Example 8) waschanged to 20 mL. As a result of ¹⁹F-NMR measurement usinghexafluorobenzene as an internal standard, it was found that theconversion was 45%, the yield was 40%, and2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 5% in a yield.

Example 9 Preparation of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4)

To a 50 mL eggplant-shaped flask equipped with a stirrer bar, benzylalcohol (0.70 g, 6.45 mmol) and tetrahydrofuran (3 mL) were added undernitrogen stream. After cooling to −20° C., n-butyllithium (1.6 M hexanesolution, 3.02 mL, 4.81 mmol) was added, followed by stirring at thesame temperature for 30 minutes.

Hexane (10 mL) was subsequently added and, after cooling to −80° C.,2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) wasadded. This was followed by further stirring at the same temperature for30 minutes, and by stirring at 0° C. for 16 hours.

After the reaction was completed, the reactant was quenched withsaturated aqueous ammonium chloride solution (10 mL), concentrated underreduced pressure, extracted with dichloromethane (10 ml×3 times),combined organic layers and dried them over sodium sulfate, filtrated,and then concentrated to give a crude product of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4) as a pale yellowsolid (1.43 g). At this stage, the conversion of CFP and yield of theproduct were determined by ¹⁹F-NMR of the crude product usinghexafluorobenzene as an internal standard, it was found that theconversion was 100%, the yield was 93%, and2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 7% in a yield.

Example 10 Preparation of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4)

To a 50 mL eggplant-shaped flask equipped with a stirrer bar, sodiumhydride (60% in oil, 0.20 g, 4.99 mmol) and tetrahydrofuran (8 mL) wereat room temperature under nitrogen stream and were stirred for 30minutes. To the mixture, benzyl alcohol (0.60 g, 5.53 mmol) was added,followed by stirring at the same temperature for 30 minutes. Hexane (20mL) was subsequently added and, after cooling to −20° C.,2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) was addedand then stirred at the same temperature for 24 hours.

After the reaction was completed, the reactant was quenched withsaturated aqueous ammonium chloride solution (10 mL), concentrated underreduced pressure, extracted with dichloromethane (10 ml×3 times),combined organic layers and dried them over sodium sulfate, filtrated,and then concentrated gave a crude product of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4) as a pale yellowsolid (1.62 g). At this stage, the conversion of CFP and yield of theproduct were determined by ¹⁹F-NMR of the crude product usinghexafluorobenzene as an internal standard, and it was found that theconversion was 100%, the yield was 91%, and2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 9% in a yield.

Example 11 Preparation of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4)

To a 50 mL eggplant-shaped flask equipped with a stirrer bar, benzylalcohol (0.55 g, 5.07 mmol) and tetrahydrofuran (2 mL) were added undernitrogen stream. After cooling to −40° C., potassiumhexamethyldisilazide (1.0 M tetrahydrofuran solution, 4.70 mL, 4.70mmol) was added, followed by stirring at the same temperature for 30minutes.

Hexane (15 mL) was subsequently added, and2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) was thenadded. The mixture was followed by further stirring at the sametemperature for 30 minutes and then by stirring at −20° C. for 36 hours.

After the reaction was completed, the reaction mixture was quenched withsaturated aqueous ammonium chloride solution (10 mL), concentrated underreduced pressure, extracted with dichloromethane (10 ml×3 times),combined organic layers and dried them over sodium sulfate, filtrated,and then concentrated gave a crude product of2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine (4) as a pale yellowsolid (1.45 g). At this stage, the conversion of CFP and yield of theproduct were determined by ¹⁹F-NMR of the crude product usinghexafluorobenzene as an internal standard, and it was found that theconversion was 98%, the yield was 95%, and2-chloro-4-benzyloxy-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 3% in a yield.

Example 12 Preparation of2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine (8)

Placed to a 50 mL eggplant-shaped flask equipped with a stirrer bar,benzenethiol (0.51 g, 4.63 mmol) and tetrahydrofuran (20 mL) were addedunder nitrogen stream. After cooling to −20° C., n-butyllithium (1.6 Mhexane solution, 2.88 mL, 4.61 mmol) was added, followed by stirring atthe same temperature for 30 minutes.

2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.00 g, 4.61 mmol) wassubsequently added. This was followed by further stirring at the sametemperature for 30 minutes and then by stirring at room temperature for16 hours.

After the reaction was completed, the reaction mixtute was quenched withsaturated aqueous ammonium chloride solution (10 mL), concentrated underreduced pressure, extracted with dichloromethane (10 ml×3 times),combined organic layers and dried them over sodium sulfate, filtrated,and then concentrated gave a crude product of2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine (8) as a white solid(1.38 g). At this stage, the conversion of CFP and yield of the productwere determined by ¹⁹F-NMR of the crude product using hexafluorobenzeneas an internal standard, it was found that the conversion was 99%, theyield was 92%, and 2-phenylthio-4-chloro-5-(trifluoromethyl)pyrimidineas a by-product was contained in an amount of 6% in a yield.

Furthermore, purification of the crude product by recrystallizationusing ethylbenzene to obtain purified2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine (8) as a white solid(1.13 g, yield=85%, purity=99%).

¹H-NMR (CDCl₃, 400 MHz) δ 8.54 (d, J=0.8 Hz, 1H), 7.60-7.45 (m, 5H).

¹⁹F-NMR (CDCl₃, 376 MHz) δ −64.32.

¹³C-NMR (CDCl₃, 100 MHz) δ 172.75, 163.29, 155.52 (q, J=5.3 Hz), 136.03,130.72, 129.77, 122.84 (q, J=271.6 Hz), 119.59 (q, J=33.8 Hz).

GC-MS (m/z): 290 (50, M⁺), 289 (100), 255 (13), 235 (7), 221 (3), 185(8), 109 (22).

Element Analysis

Calculated: carbon (45.45%), hydrogen (2.08%), nitrogen (9.64%)

Measured: carbon (45.33%), hydrogen (2.08%), nitrogen (9.62%)

Example 13 Preparation of2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine (8)

A crude product (1.27 g) was obtained as a white solid by performing thesame procedures as those in Example 12 using the same reactor as that inExample 12, except that the amount of tetrahydrofuran was changed from20 mL to 10 mL. At this stage, the conversion of CFP and yield of theproduct were determined by ¹⁹F-NMR of the crude product usinghexafluorobenzene as an internal standard, it was found that theconversion was 100%, the yield was 89%, and2-phenylthio-4-chloro-5-(trifluoromethyl)pyrimidine as a by-product wascontained in an amount of 5% in a yield.

Example 14 Preparation of2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine (8)

A crude product (1.21 g) was obtained as a white solid by performing thesame procedures as those in Example 12 using the same reactor as that inExample 12, except that sodium hydride (60% in oil, 0.20 g, 4.99 mmol)was used instead of n-butyllithium (1.6 M hexane solution, 2.88 mL, 4.61mmol) and that the reaction was allowed to proceed at 0° C. for 24hours. At this stage, the conversion of CFP and yield of the productwere determined by ¹⁹F-NMR of the crude product using hexafluorobenzeneas an internal standard, it was found that the conversion was 94%, theyield was 84%, and 2-phenylthio-4-chloro-5-(trifluoromethyl)pyrimidineas a by-product was contained in an amount of 8% in terms of yield.

Example 15 Preparation of2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine (8)

A crude product (1.26 g) was obtained as a white solid by performing thereaction procedures as those in Example 12 using the same reaction unitas that in Example 12, except that benzenethiol (0.64 g, 5.79 mmol) wasused instead of benzenethiol (0.51 g, 4.63 mmol), that potassiumhexamethyldisilazide (1.0 M toluene solution, 4.63 mL, 4.63 mmol) wasused instead of n-butyllithium (1.6 M hexane solution, 2.88 mL, 4.61mmol), and that the reaction was allowed to proceed at −10° C. for 36hours. At this stage, the conversion of CFP and yield of the productwere determined by ¹⁹F-NMR of the crude product using hexafluorobenzeneas an internal standard, it was found that the conversion was 98%, theyield was 90%, and 2-phenylthio-4-chloro-5-(trifluoromethyl)pyrimidineas a by-product was contained in an amount of 4% in terms of yield.

INDUSTRIAL APPLICABILITY

2-(2,2,2-trifluoroethoxy)-4-chloro-5-(trifluoromethyl)pyrimidine,2-benzyloxy-4-chloro-5-(trifluoromethyl)pyrimidine,2,4-bis(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrimidine, and2-chloro-4-phenylthio-5-(trifluoromethyl)pyrimidine according to thepresent invention, which are novel, can be used as introducers of a5-(trifluoromethyl)pyrimidine skeleton and as intermediates forsynthesis of various pharmaceuticals and electronic materials.

The invention claimed is:
 1. The A 5-(trifluoromethyl)pyrimidinederivative represented by the following Formula 3:


2. A method for producing the 5-(trifluoromethyl)pyrimidine derivativeaccording to claim 1, the method comprising reacting2,4-dichloro-5-(trifluoromethyl) pyrimidine with a metal2,2,2-trifluoroethoxide.
 3. A method for producing the5-(trifluoromethyl)pyrimidine derivative according to claim 1, themethod comprising reacting 2,4-dichloro-5-(trifluoromethyl) pyrimidinewith a metal salt of 2,2,2-trifluoroethanol.
 4. The method for producingthe 5-(trifluoromethyl)pyrimidine derivative according to claim 3,wherein the metal salt is a lithium salt, a sodium salt, or a potassiumsalt.
 5. The A 5-(trifluoromethyl)pyrimidine derivative represented bythe following Formula 4:


6. A method for producing the 5-(trifluoromethyl)pyrimidine derivativeaccording to claim 5, the method comprising reacting2,4-dichloro-5-(trifluoromethyl)pyrimidine with a metal salt of benzylalcohol in a mixed solvent of tetrahydrofuran and hexane.
 7. The methodfor producing the 5-(trifluoromethyl)pyrimidine derivative according toclaim 6, wherein the metal salt is a lithium salt, a sodium salt, or apotassium salt.